Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the down-modulation of IFN regulatory factor-1 (IRF-1)

VELASQUEZ, LIS N.; MILILLO, M. AYELÉN; DELPINO, VICTORIA; TROTTA, ALDANA; FERNANDEZ, PABLO; POZNER, ROBERTO G.; LANG, ROLAND; BALBOA, LUCIANA; GIAMBARTOLOMEI, GUILLERMO; BARRIONUEVO, PAULA

JOURNAL OF LEUKOCYTE BIOLOGY

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2017 vol. 101 p. 759 - 773

0741-5400

Brucella abortus is an intracellular pathogen capable of surviving inside macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4+ T cell responses it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC-II molecules on human monocytes and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms whereby B. abortus is able to down-regulate the expression of MHC-II remained to be elucidated. In this study we demonstrated that B. abortus infection inhibits the IFN-γ-induced transcription of CIITA and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC-II; it also inhibited the expression of invariant-chain-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as B. abortus infection. IL-6 contributes to these down-regulatory phenomena. In addition, B. abortus and its lipoproteins through IL-6 secretion induced the transcription of the negative regulators of IFN-γ signaling SOCS-1 and SOCS-3 without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL-6 inhibit the expression of IRF-1, a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way may prevent recognition by T cells; establishing a chronic infection.